Protocol for the National Nurse Health Study (NNHS): a web-based ambispective cohort study

IntroductionThe physical and mental health of nurses may significantly impact the entire medical care group and directly affect the quality of medical services. Due to the intense emotional involvement and often problematic working conditions that characterise their profession, nurses appear to be especially susceptible to a complex set of stressors with repercussions to their health. Several landmark studies of nurses have provided an abundance of evidence on risk factors that influence the health status of nurses. However, few studies have investigated the health status of nurses who work in high-intensity work environments in China. The National Nurse Health Study (NNHS) objective is to build an ambispective cohort to gather web-based information on early-life events, daily habits, occupational and environmental risk factors, and health outcomes of a specific subset of healthcare professionals of Chinese nurses.Methods and analysisNNHS, which was developed at a tertiary hospital in Beijing, China, is a research initiative that enrolls registered nurses working at Peking University Third Hospital. A web-based self-administered system was designed to collect health-related data and link them with previous physical examination data. During the study period, participants with signed informed consent will be invited to annually repeat a similar procedure.Ethics and disseminationThe NNHS research protocol was approved by the Institutional Ethics Committee and provides promising data that contribute to the understanding of pathophysiological links between early-life events, body composition, gut microbiota, and inflammatory and metabolic risk profiles. Moreover, the combination of a user-friendly tool with the innovative purposes of the NNHS offers a remarkable resource to test hypotheses about mechanisms of diseases, including work stress, and further plan preventive programmes in public health.Trial registration numberThe study was registered on Clinicaltrials.gov (https://clinicaltrials.gov/ct2/show/NCT04572347) and the China Cohort Consortium (http://chinacohort.bjmu.edu.cn/project/102/).

Maternal Emulsifier P80 Intake Induces Gut Dysbiosis in Offspring and Increases Their Susceptibility to Colitis in Adulthood

ABSTRACT Early life events can lead to multiple diseases in adulthood. Previous studies suggested that polysorbate 80 (P80) as a widely used emulsifier in pharmaceutical formulations and food industries could impair the intestinal barrier. However, whether maternal P80 (MP80) exposure could affect the long-term health of offspring remains unknown. In this study, we found that maternal P80 intake could retard intestinal development, disrupt the intestinal barrier, and cause low-grade intestinal inflammation in 3-week-old offspring. 16S rRNA sequencing and correlation analysis revealed that Mucispirillum, Clostridium XI, and Parabacteroides, which positively correlated with intestinal proliferation and differentiation, were decreased in the maternal P80 group. Interestingly, the increase in some harmful bacteria, including Proteobacteria, Helicobacteraceae, Campylobacterales, and Desulfovibrionales, persisted from the weaning period to adulthood (3 to 8 weeks). Furthermore, a fecal microbiota transplantation assay showed that the mice gavaged with feces from 3-week-old offspring of the MP80 group presented more severe intestinal inflammation and barrier disruption than the mice that received feces from the offspring of the control group. Finally, maternal P80 intake remarkably aggravated the structural disorder of intestinal crypt, increased proinflammatory factors, and exacerbated dextran sulfate sodium (DSS)-induced colitis in adulthood. Conclusively, maternal P80 intake could induce gut dysbiosis and promote colitis susceptibility in adulthood. This study provides new insights into the prevention of inflammatory bowel disease (IBD). IMPORTANCE The main findings of this research showed that maternal P80 intake could disrupt the intestinal barrier, induce gut dysbiosis, and promote colitis susceptibility in adulthood. This study will enhance understanding of the prevention of IBD.

Fetal-Derived Immune Cells at the Roots of Lifelong Pathophysiology

Tissue-resident innate immune cells exert a wide range of functions in both adult homeostasis and pathology. Our understanding of when and how these cellular networks are established has dramatically changed with the recognition that many lineages originate at least in part from fetal sources and self-maintain independently from hematopoietic stem cells. Indeed, fetal-derived immune cells are found in most organs and serous cavities of our body, where they reside throughout the entire lifespan. At the same time, there is a growing appreciation that pathologies manifesting in adulthood may be caused by adverse early life events, a concept known as “developmental origins of health and disease” (DOHaD). Yet, whether fetal-derived immune cells are mechanistically involved in DOHaD remains elusive. In this review, we summarize our knowledge of fetal hematopoiesis and its contribution to adult immune compartments, which results in a “layered immune system.” Based on their ontogeny, we argue that fetal-derived immune cells are prime transmitters of long-term consequences of prenatal adversities. In addition to increasing disease susceptibility, these may also directly cause inflammatory, degenerative, and metabolic disorders. We explore this notion for cells generated from erythro-myeloid progenitors (EMP) produced in the extra-embryonic yolk sac. Focusing on macrophages and mast cells, we present emerging evidence implicating them in lifelong disease by either somatic mutations or developmental programming events resulting from maternal and early environmental perturbations.

Changes Induced by Mind–Body Intervention Including Epigenetic Marks and Its Effects on Diabetes

Studies have evidenced that epigenetic marks associated with type 2 diabetes (T2D) can be inherited from parents or acquired through fetal and early-life events, as well as through lifelong environments or lifestyles, which can increase the risk of diabetes in adulthood. However, epigenetic modifications are reversible, and can be altered through proper intervention, thus mitigating the risk factors of T2D. Mind–body intervention (MBI) refers to interventions like meditation, yoga, and qigong, which deal with both physical and mental well-being. MBI not only induces psychological changes, such as alleviation of depression, anxiety, and stress, but also physiological changes like parasympathetic activation, lower cortisol secretion, reduced inflammation, and aging rate delay, which are all risk factors for T2D. Notably, MBI has been reported to reduce blood glucose in patients with T2D. Herein, based on recent findings, we review the effects of MBI on diabetes and the mechanisms involved, including epigenetic modifications.

Early Adversity and Neurodevelopment

This chapter addresses the impact of early childhood adversity on the developing brain and nervous system. The author provides a critical review of the Adverse Childhood Experiences study and expands the concept of early adversity to include systemic and environmental stressors and a focus on resilience in addition to potential pathology. Particular focus is given to reviewing contemporary neuroscience research on the influence of negative early life events, including impacts on brain structure, function, connectivity, epigenetic processes, and inflammation. The author identifies overarching findings while also acknowledging limitations of the current science and the difficulties inherent in practitioners' translating primary brain research into school-based interventions. Some ideas for practical applications of the science are provided.

NURR1 Alterations in Perinatal Stress: A First Step towards Late-Onset Diseases? A Narrative Review

Perinatal life represents a delicate phase of development where stimuli of all sorts, coming to or from the mother, can influence the programming of the future baby’s health. These stimuli may have consequences that persist throughout adulthood. Nuclear receptor related 1 protein (NURR1), a transcription factor with a critical role in the development of the dopaminergic neurons in the midbrain, mediates the response to stressful environmental stimuli in the perinatal period. During pregnancy, low-grade inflammation triggered by maternal obesity, hyperinsulinemia or vaginal infections alters NURR1 expression in human gestational tissues. A similar scenario is triggered by exposure to neurotoxic compounds, which are associated with NURR1 epigenetic deregulation in the offspring, with potential intergenerational effects. Since these alterations have been associated with an increased risk of developing late-onset diseases in children, NURR1, alone, or in combination with other molecular markers, has been proposed as a new prognostic tool and a potential therapeutic target for several pathological conditions. This narrative review describes perinatal stress associated with NURR1 gene deregulation, which is proposed here as a mediator of late-onset consequences of early life events.

Gut metagenomics discriminates unique microbial signatures in diverse symptomatic profiles with attention-deficit/hyperactivity disorder

BackgroundAttention-deficit/hyperactivity disorder (ADHD) is a highly heterogeneous psychiatric disorder that can be divided into inattentive (I-ADHD), hyperactive-impulsive (HI-ADHD), and combined (C-ADHD) subtypes. Different early life events and environmental factors correlated with the gut microbiota community have been implicated in the development of ADHD. However, whether different ADHD symptomatic presentations are associated with distinct microbiota composition and function still unknown. Therefore, we carried out metagenomic analysis from 207 subjects to characterize the gut microbial profiles in ADHD and subgroup patients.ResultsThe current study revealed that the gut microbiota composition (beta diversity) can be effectively distinguished between C-ADHD patients and HCs, but not I-ADHD patients and HCs, nor general ADHD patients and HCs. Features include underrepresentation of 8 species belonging to the genus Bacteroides and enrichment of 5 species of Bifidobacterium and Prevotella in general ADHD patients (all p < 0.05). Eight of the above species became progressively reduced (ovatus, thetaiotaomicron, intestinalis, cellulosilyticus, and fluxus belonging to the genus Bacteroides) or enriched (Prevotella_copri, Prevotella_buccae and Bifidobacterium_breve) from healthy controls (HCs) to I-ADHD and C-ADHD patients. Predicted metabolic functions from these distinguished gut microbial markers described a certain compensatory host metabolism in ADHD and subgroup patients. Particularly, pyridoxal 5'-phosphate (a dominant vitamin B6 active type) biosynthesis pathways were significantly reduced in C-ADHD patients, because serum vitamin B6 deficiency in ADHD patients was found previously. Of note, we identified diverse virulence factor and antibiotic resistance from the gut microbiota of ADHD patients. The abundance of antibiotic resistance ontology ANT(9)-Ia positively correlated with the abundance of Prevotella_amnii, which was enriched in ADHD patients. Moreover, species-based bacterial markers were used to construct classifiers and achieved a higher AUC of 0.87 in C-ADHD vs. HC than that in ADHD vs. HC (AUC = 0.84).ConclusionsThese findings uncover alterations in microbial composition in subgroup patients and provide potential biomarkers for diagnosis different symptomatic presentations for ADHD.Trial registration: ClinicalTrials.gov, NCT03447223. Registered 27 February 2018, https://clinicaltrials.gov/ct2/show/NCT03447223?term=03447223&draw=2&rank=1

A22 ADVERSE EARLY LIFE EVENTS ARE COMMON IN PATIENTS WITH FUNCTIONAL AND ORGANIC GASTROINTESTINAL DISORDERS

Background Stressful events in childhood have been associated with the development of functional gastrointestinal (GI) disorders in adulthood, especially irritable bowel syndrome. The influence of early life adverse events in patients with common organic disorders, such as celiac disease and inflammatory bowel disease (IBD), has been poorly investigated. Aims To evaluate the frequency of early life adverse events in patients with organic and functional gastrointestinal disorders compared to healthy controls. Methods Adult patients with an established diagnosis of IBS (Rome IV criteria), celiac disease and inflammatory bowel disease (IBD) attending a tertiary medical center, as well as healthy volunteers were interviewed by a psychologist. Early life adverse events were assessed during the semi-structured interview using a modified version of the Adverse Childhood Experience (ACE) questionnaire. Number of early life events and the presence of GI and extraintestinal symptoms based on a 10-point Likert scale were quantified. Data are presented as Median (IQR) and n (%). Statistical analysis was performed using Mann-Whitney and Fisher’s exact tests as appropriate. Results Sixty-eight patients (18 IBS, 28 celiac, 22 IBD) and 23 healthy controls were enrolled in the study. Patients with IBS, celiac disease and IBD had increased number of early life events compared with healthy controls (6.5 (4.8–8.3), 5.0 (3.0–9.0), 6.0 (4–8.3) vs 2.0 (1.0–4.0) respectively, p&lt;0.0001). Patients reported a higher number of mental disorders in their mothers (IBS p=0.01; celiac disease p=0.01; IBD p=0.001) and increased number of close family member abusing alcohol or drugs during their childhood (IBS p=0.01; celiac p=0.02; IBD p=0.02) compared to healthy controls. History of sexual abuse was higher in patients with IBS (p=0.01), while history of verbal abuse was higher in patients celiac disease and IBD (p=0.003 and p=0.001, respectively) compared to healthy controls. The number of early life adverse events was strongly correlated with number of GI (r= 0.91; p=0.01) and extra-intestinal (r=0.87; p=0.02) symptoms, but not with symptoms severity. Most patients with IBS (83.3%), celiac disease (89.3%) and IBD (85.7%) reported stressful events before the onset of their disease. Conclusions Adverse events in childhood are frequent in patients with chronic GI disorders, both of functional and organic origin. Furthermore, stressful events often precede their diagnosis. These data strongly suggest that better psychosocial assessment in patients with chronic GI disorders is needed to improve their overall management. Funding Agencies None